GPX4 Inhibition Contributes to NLRP3-Mediated Pyroptosis and Cognitive Impairment in Ketamine-Exposed Neonatal Rats.
Hui Bai, Shan Du, Di Qiu, Siyao Li, Ruifeng Gao, Zhiheng Zhang
Molecular Neurobiology May 23, 2025 DOI: 10.1007/s12035-025-05042-w (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | 7-day-old rats and PC12 and HAPI cell lines |
| Interventions | Ketamine N-acetylcysteine (NAC) RSL3 |
| Topics | Ketamine Esketamine |
| Keywords | Developing rats Gpx4 Hippocampal injury Pyroptosis Anesthesia research Developmental biology Cell death mechanisms Brain injury |
| Citations | 4 |
| Key findings | GPX4 acts as a negative regulator of pyroptosis in ketamine-induced hippocampal damage and cognitive dysfunction in developing rats. |
Abstract
Increasing evidence reveals that multiple or prolonged exposure to ketamine causes hippocampal damage and cognitive dysfunction. However, the critical mechanisms underlying ketamine-induced neurotoxicity in the developing brain remain elusive. The present study was designed to investigate the role of GPX4 in ketamine-induced pyroptosis and cognitive dysfunction in the developing rat hippocampus. To achieve this goal, we conducted Western blotting, ELISA tests, histopathological analysis, Morris water maze tests, cell viability assays, and biochemical analyses on PC12 cells, HAPI cells, and 7-day-old rats. Additionally, N-acetylcysteine (NAC) and RSL3 were administered prior to continuous ketamine exposure. Our findings indicate that GPX4 inhibition by RSL3 enhances lipid peroxidation and mitochondrial damage, activates NLRP3/caspase-1 axis-dependent pyroptosis, and exacerbates hippocampal damage and cognitive dysfunction following ketamine exposure, while NAC effectively mitigates the effects of RSL3. Collectively, our in vivo and in vitro results support the notion that GPX4 may serve as a negative regulator of pyroptosis in ketamine-induced hippocampal damage and cognitive dysfunction. Our study proposes a novel strategy for treating ketamine-induced neurotoxicity through upregulating GPX4 expression.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |